Xpo7 negatively regulates Hedgehog signaling by exporting Gli2 from the nucleus

Cell Signal. 2021 Apr:80:109907. doi: 10.1016/j.cellsig.2020.109907. Epub 2020 Dec 28.

Abstract

Dynamic bidirectional transport between the nucleus and the cytoplasm is critical for the regulation of many transcription factors, whose levels inside the nucleus must be tightly controlled. Efficient shuttling across the nuclear membrane is especially crucial with regard to the Hedgehog (Hh) pathway, where the transcriptional signal depends on the fine balance between the amounts of Gli protein activator and repressor forms in the nucleus. The nuclear export machinery prevents the unchecked nuclear accumulation of Gli proteins, but the mechanistic insight into this process is limited. We show that the atypical exportin Xpo7 functions as a major nuclear export receptor that actively excludes Gli2 from the nucleus and controls the outcome of Hh signaling. We show that Xpo7 interacts with several domains of Gli2 and that this interaction is modulated by SuFu, a key negative regulator of Hh signaling. Our data pave the way for a more complete understanding of the nuclear shuttling of Gli proteins and the regulation of their transcriptional activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • CRISPR-Cas Systems / genetics
  • Cell Line
  • Cell Nucleus / metabolism*
  • Exportin 1 Protein
  • Hedgehog Proteins / metabolism
  • Humans
  • Karyopherins / antagonists & inhibitors
  • Karyopherins / genetics
  • Karyopherins / metabolism
  • Mice
  • RNA Interference
  • RNA, Guide, CRISPR-Cas Systems
  • RNA, Small Interfering / metabolism
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Signal Transduction*
  • Transcription, Genetic
  • Zinc Finger Protein Gli2 / genetics
  • Zinc Finger Protein Gli2 / metabolism*
  • ran GTP-Binding Protein / antagonists & inhibitors
  • ran GTP-Binding Protein / genetics
  • ran GTP-Binding Protein / metabolism*

Substances

  • Hedgehog Proteins
  • Karyopherins
  • RNA, Small Interfering
  • RanGTP-binding protein 16
  • Receptors, Cytoplasmic and Nuclear
  • Zinc Finger Protein Gli2
  • ran GTP-Binding Protein